2-(cycloaliphatic-alkyl-aminomethyl)-benzodioxanes



United States Patent Delaware I No Drawing. Filed Apr. 30, 1963, Ser.No. 276,993

' 12 Claims. (Cl.260--340.3)

The present invention relates to 1,4-benzodioxane derivatives. Moreparticularly, it concerns Z-aminornethyl- 1,4-benzodioxanes of theformula in which R represents a 2-(l,4-benzodioxanyl) radical, n standsfor a whole number from one to seven, and R represents a cycloaliphaticradical, or salts of such comin which R stands primarily for hydrogen,but may also represent an aliphatic radical, such as lower alkyl, e.g.

methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutylfi secondary butyland the like, and Ph represents a 1,2 phenylene (o-phenylene) radical,such as 1,2-phenylene or 1,2-phenylene substituted by one or more thanone substituent, which may be attached to any of the four positionsavailable for substitution in a 1,2-phenylene radical. Substituentsattached to the 1,2-phenylene radi-- cal are, for example, an aliphatichydrocarbon radical, such as lower alkyl, e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl and the like, hydroxyl, etherified hydroxyl,particularly lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butyloxy and the like, as well as lower alkenyloxy, e.g.allyloxy, 2-rnethyl-allyloxy and the like, lower alkylene-dioxy, e.g.methylenedioxy, 1,1-ethylencdioxy and the like, cycloalkyloxy, in whichcycloalkyl has from three to eight, preferably from five to six, carbonatoms, e.g. cyclopentyloxy, cyclohexyloxy and the like, carbocyclicaryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenoxy and thelike, carbocyclic aryl-aliphatic etherified hydroxyl, such as monocycliccarbocyclic aryllower alkoxy, for example, phenyl-lower alkoxy, e.g.benzyloxy, l-phenylethoxy, 2-phenylethoxy and the like, esterifiedhydroxyl, especially halogeno (representing hydroxyl esterified by ahydrohalic acid), e.g. fluoro, chloro, brorno and the like,trifluorornethyl, mercapto, etherified rnercapto, such as loweralkyl-rnercapto, e.g. methylrnercapto, ethylmercapto and the like,nitro, amino, such as N,N-di-lower alkyl-arnino, e.g.N,N-din1ethylamino, N- ethyl-N-methyl-ainino, N,N-diethylamino and thelike, or N-acylamino, such as N-lower alkanoyl-arnino, e.g. N-acetylamino, N-propionylamino, N-pivaloylarnino and the like, orN-carbocyclic aroyl-arnino, e.g. N-benzoylamino and the like, orparticularly acyl, such as, for example,

. lower alkanoyl, e.g. acetyl, propionyl, butyryl, isobutyryl,

pivaloyl and the like, as well as carbocyclic aroyl, such as rnonocycliccarbocyclic aroyl, e.g. benzoyl and the like, carbocyclic aryl-loweralkanoyl, such as rnonocyclic carbocyclic aryl-lower alkauoyl, forexample, phenyl-lower alkanoyl, e.g. phenylacetyl and the like, or anyother analogous, suitable substituent,

Substituted 1,2-phenylene groups are, for example, aliphaticsubstituted-l,2-phenylene, such as lower alkyl-l,2- phenylene, e.g.methyl-1,2-phenylene (such as B-methyl- 1,2-phenylene,4-methyl-l,2-phenylene, 4,5-dimethyl-1,2-

3,157,674 Patented Nov. 17, 1964 "ice phenylene and the like),ethyl-1,2-phenylene (such as 4- ethyl-l,2-phenylene and the like),n-propyl-l,2-phenylene (such as 4-n-propyl-1,2-phenylene and the like),isopropyl- 1,2-phenylene (such as 3-is0propyl-1,2-phenyleue and thelike), or any other analogous lower alkyl-1,2-phenylene radical,hydroxy-1,2-phenylene (such as 3-hydroXy-1,2- phenylene,4-hydroxy-1,2-phenylene and the like), etherified hydroxy-LZ-phenylene,such as lower alkoxy-1,2-,

phenylene, e.g. methoxy-1,2-phenylene (such as 3-n1ethoxy-1,2-phenylene,4-rnethoxy-l,2-phenylene, 3,4-dimethoxy-1,2-pl1enylene and the like),ethoxy-1,2-phenylene (such as 3-ethoxy-l,2-phenylene,4-ethoxy-l,2-phenylene, 3,6-diethoxy-1,2-phenylene and the like),n-propyloxy-1,2- phenylene (such as 4-n-propyloxy-1,2-phenylene and thelike), isopropyloxy-1,2-phenylene (such as 3-isopropyloxy-1,2-phenyleneand the like), n-butyloxy-l,2-phenylene (such as4-n-butyloxy-1,2-phenylene and the like), or any other analogous loweralkoxy-1,2-phenylene radical, lower alkenyloxy-1,2-phenylene, e.g.allyloxy-l,2- phenylene (such as 3-allyloxy-l,2-phenylene, 4-allyloxy-1,2-phenylene and the like), or any other analogous loweralkenyloxy-1,2-phenylene radical, lower alkylene-dioxy- 1,2-phenylene,e.g. methylenedioxy-l,2-phenylene (such as3,4-niethylenedioxy-1,2-phenylene and the like), or any other analogouslower alkylenediox -1,2-phenylene radical, cycloalkyloxy-1,2-phenylene,in which cycloalkyl has from three to eight, preferably from five to sixcarbon atoms, e.g. cyclopentyloxy-1,2-phenylene (such as3-cyclopentyloxy-l,2-phenylene and the like), cyclohexyloxy-1,2-phenylene (such as 3-cyclohexyloxy-1,2 phenyleue' and the like) orany other analogous cycloalkyloxy-1,2 phenylene radical,'monocycliccarbocyclic aryloxy-l,2- phenylene, e.g. phenoxy-l,2-phenylene (such as3-phenoxy-l,2-phenylene and the like) or any other analogous monocycliccarbocyclic aryloxy-l,2-phenylene radical, monocyclic carbocyclicaryl-lower alkoxy-l,2-phenylene, such as phenyl-loweralkoxy-'l,2-phenylene, e.g. benzyloxy-l,2-phenylene (such as3-benzyloxy-1,2-phenylene, 4- benzyloxy-1,2-phenylene and the like),2-phenylethoxy- 1,2-phenylene [such as 3-(2-phenylethoxy)-l,2-phenyleneand the like] or any other analogous monocyclic carbocyclic aryl-loweralkoxy-l,2-phenylene radical, esterified hydroxy-1,2-phenylene,particularly halogeno-l,2-phenylene, e.g. fiuoro-1,2-phenylene (such as3-fluoro-l,2-phenylene, 4-luoro-1,2-phenylene and the like), chloro l,2-phenylene (such as 3-chloro-l,2-phenylene, 4-chloro-1,2-v phenylene,4,5-dichloro-1,Z-phenylene, 3,4,5,6-tetrachloro- 1,2-phenylene and thelike), bromo-l,2-phenylene (such as 4-brorno-l,2-phe11ylene,3,6-dibrom-l,2-phenylene and the like), or any other analogoushalogeno-l,2-phenylene or esterified hydroxy-1,2-phenylene radical,trifluoromethyl-l,2-phenylene (such as 4-trifluorornethyl-1,2-phenyleneand the like, mercapto-LZ-phenylene (such as 4-mercaptoe 1,2-phenyleneand the like), etherified rnercapto-1,2-phenylene, such as loweralkyl-mercapto-l,2-phenylene, e.g. methylmercapto-l,2-phenylene (such as4-n1ethylmercapto-l,2-phenylene and the like), ethylmercapto-l,2-phenylene (such as 3-ethylmercapto-1,2-phenylene and the like), or anyother analogous lower alkyl-mercapto- 1,2-phenylene radical,nitro-1,2-pheny1e11e (such as 3- nitro-l,2-phenylene,4-nitro-l,2-phenylene and thelike), N,N-di-loweralkyl-amino-1,2-phenylene, e.g. N,N-dimethylamino-1,2-phenylene (such as3-N,N-dimethylarnino-l,2-phenylene, 4 N,N dirnethylaznino-l,2-phenyleneand the like), N-ethyl-N-methyl-amino-l,2-phenylene (such as4-N-ethyl-N-methyl-amino-1,2-phenylene and the like),N,N-diethylamino-1,2-phenylene (such as 4-N,N-diethylamino-1,2-phenylene and the like), or any other N,N-dilow eralkyl-amino-l,Z-phenylene radical, N- acyl-amino-l,2-phenylene, such asN-lower alkanoyl-arnino-l,2-phenylene, e.g. N-acetylarnino-l,2-phenylene(such as 4-N-acetyl-amino-1,2-phenylene and the like), N-

pivaloylamino-1,2-phenylene (such as 4-N-pivaloylamino- 1,2-phenyleneand the like), as well as N-benzoylamino- LZ'phenylene (such as4-N-benzoylamino-1,2-phenylene and the like), or any other analogousN-acyl-amino-l,2- phenylene radical, or particularly acyl-l,2-phenylene,such as lower alkanoyl-1,2-phenylene, e.g. acetyl-1,2-phenylone (such as3-acetyl-l,2-phenylene, 4-acetyl-1,2-phenylene and the like),propionyl-l,Z-phenylene-1,2-phenylene (such as 3-propionyl-l,Z-phenyleneand the like), butyryl- 1,2-phenylene (such as 4-butyryi-l,2-phenyleneand the like), pivaloyl-1,2-phenylene (such as 3-pivaloyl-l,2-phenyleneand the like) or any other analogous lower alkanoyl- 1,2-phenyleneradical, monocyclic carbocyclic aroyl-l,2- phenylene, e.g.benzoyl-l,2-phenylene (such as 3-benzoyl- 1,2-phenylene,4-benzoyl-l,2-phenylene and the like) or any other analogous monocycliccarbocyclic aroyI-l,2- phenylene radical, monocyclic carbocyclicaryl-lower alkanoyl-1,2-phenylene, such as phenyl-lower alkanoyl-1,2-phenylene, e.g. phenylacetyl-1,2-phenylene (such as 3-phenylacetyl-l,2-phenylene and the like) or any other analogousmonocyclic aryl-lower alkanoyl-l,2-phenylene radical, or any equivalentsubstituted 1,2-phenylene radical.

The alkylene radical represented by C H in the above formula, in whichit may stand for a whole number from one to seven, has preferably fromone to four carbon atoms (it stands, therefore, preferably for a Wholenumber from one to four), which carbon atoms may be arranged in astraight or a branched carbon chain. Such alkylene radicals may berepresented by methylene, 1,1-ethylene, 1,2-ethylene,l-methyl-l,2-ethylene, 2-methyl-l,2-ethylene, 1,3-propylene,1,4-butylene and the like, as well as 1,4-pentylene, 1,5-pentylene,1,6-hexylene, 1,7-heptylene and the like.

The cycloaliphatic radical R is preferably saturated and represents,threfore, primarily cycloalkyl. However, it may also contain one or morethan one double bond, depending on the number of ring carbon atoms. Acycloalkyl group may have from three to eight, preferably from five tosix, ring carbon atoms. Cycioalkyl is, therefore, primarily cyclopentylor cyclohexyl, as well as cyclopropyl, cyclobutyl, cycloheptyl orcyclo-octyl. A cycloaliphatic radical having one or more than one doublebond is particularly a cycloalkenyl group, which has from five to eight,preferably from five to six, carbon atoms;

cycloalkenyl groups are, for example, l-cyclopentenyl, 2

cyclopentenyl, 3-cyclopentcnyl, l-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl and the like, as well as 3-cycloheptenyl, Z-cyclo-octenyland the like. The cycloaliphatic radicals are preferably unsubstituted,but may contain substituents, such as, for example, lower alkyl, e.g.methyl, ethyl, n-propyl, isopropyl and the like, or functional groups,such as halogeno, e.g. chloro, bromo and the like, lower alkoxy, e.g.methoxy, ethoxy and the like, or any other suitable functional group.

Salts of the new compounds of this invention are particularly non-toxic,pharmaceutically acceptable acid addition salts, for example, those withinorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoricacids and the like, with organic carboxylic acids, e.g. formic, acetic,propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic,dihydroxyrnaleic, benzoic, phenylacetic, 4- aminobenzoic,4-hydroxybenzoic, cinnamic, mandelic, salicyclic, 4-aminosalicyclic,Z-phenoxybenzoic, Z-acetoxy-benzoic acid and the like, or with organicsulfonic acids, e.g. methane sulfonic, ethane sulfonic, Z-hydroxyethanesulfonic, ethane l,2-disulfonic acid, benzene sulfonic, p-toluenesulfonic acid and the like.

The compounds of this invention have long-lasting antihypertensiveproperties and can, therefore, be used as antihypertensive agents, forexample, in renal hypertension or similar hypertensive conditions. Apartfrom some ataxic properties, the compounds of this invention arevirtually free from adverse side effects usualiy associated V in which Rrepresents cycloalkyl having from three to benz-acetyl-Z-(N-cycloalkyl-lower eight carbon atoms and stands primarily forcyclopentyl or cyclohexyl, n represents a whole number from one to four,and the pharmameutically acceptable acid addition salts of suchcompounds.

Another group of compounds, which have outstanding and long-lastingantihypertensive effects and are virtually free from any unwarrantedadrenolytic side effects, is represented by the formula in which R andthe letter 11 have the previously-given meaning, and in which R standsfor lower alkanoyl, and the pharmaceutically acceptable acid additionsalts thereof. This group of compounds may be represented byalkyl-amino-methyl 1,4-benzodioxanes, in which cycloalkyl has from fiveto six ring carbon atoms, lower alkyl has from one to four carbon atoms,and acetyl is attached to the carbocyclic aryl portion of the1,4-benzodioxane nucleus, or pharmaceutically acceptable acid additionsalts thereof.

The new compounds of this invention may be used in the form ofpharmaceutical preparations, which contain the new compounds or thesalts thereof in admixture with a pharmaceutical organic or inorganic,solid or liquid carrier suitable for enteral or parenteraladministration. For making up the preparations there are employedsubstances which do not react with the new compounds, such as water,gelatine, lactose, starches, stearic acid, magnesium steal-ate, stearylalcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol,polyalkylene glycols, petroleum jelly or any other known carrier usedfor pharmaceutical preparations. These may be in solid form, forexample, as tablets, dragees, capsules and the like, or in liquid form,for example, as solutions, suspensions, emulsions and the like, and, ifdesired, may contain auxiliary substances, such as preserving,stabilizing, wetting, emulsifying agents and the like, salts for varyingthe osmotic pressure, buffers, etc. They may also contain, incombination, other pharmaceutically useful substances.

The compounds of this invention may be prepared according to methodsknown per so. I prefer to manufacture these compounds by treating acycloaliphatic hydrocarbon-lower alkyl-amine, particularly an amine ofthe formula R -(C,,H )NH in which R and the letter n have thepreviously-given meaning, with a reactive ester of a2-(l,4-benzodioxanyl)methanol, particularly with a compound of theformula R CH X, in which R has the previously-given meaning, and Xrepresents a reactive esterified hydroxyl group, and, if desired,converting a resulting salt into a free compound or into another salt,and/or, if desired, converting a free compound into a salt thereof,and/or, if desired, introducing a substituent into the carbocyclic arylportion of the 1,4-benzodioxane nucleus, and/or, if desired, convertinga substituent attached to the carbocyclic aryl portion of the1,4-henzodioxane nucleus into another substituent.

A reactive esterified hydroxyl group, such as the group X is a reactiveester of a 2-(l,4-benzodioxanyi)methaaol,

such as a compound of the formula R CH -X, is particularly a hydroxylgroup esterified with a strong inorganic acid, such as a mineral acid,particularly a hydrohalic acid, e.g. hydrochloric, hydrobromic,hydriodic acid and the like, as well as sulfuric acid and the like, or astrong organic acid, particularly a strong organic sulfonic acid, suchas a monocyclic carbocyclic aryl sulfonic acid, e.g. p-toluene sulfonicacid and the like, or a lower alkane sulfonic acid, e.g. methanesulfonic acid, ethane sulfonic acid and the like. The group X in theabove formula is primarily represented by halogeno having an atomicweight greater than 19, such as chloro, bromo or iodo.

The reaction is preferably carried out by treating the amine with thereactive ester of the 2-(1,4-benzodioXanyl)-methanol compound in such away that an excess of the amine is always present. Alcohols, such aslower alkanols, e.g. methanol, ethanol and the like, or any othersuitable inert diluent may serve as solvents. If necessary, an alkalinereagent, such as an alkali metal carbonate, e.g. sodium or potassiumcarbonate and the like, or an organic base, e.g. pyridine and the like,may be used to neutralize the generated acid.

The reaction is preferably performed at an elevated temperature, ifnecessary, in a closed vessel under pressure and/or in the atmosphere ofan inert gas, e.g. nitrogen.

The starting materials used in the above reaction are known or may beprepared according to methods used for the preparation of the knowncompounds.

The compounds of this invention may also be prepared by reacting a2-(1,4-benzodioxanyl)methyl-amine, particularly a compound of theformula R CH -NH in which R has the previously-given meaning, with areactive ester of a cycloaliphatic hydrocarbon-lower alkanol,particularly with a compound of the formula R (CnH )X, in which R X andthe letter n have the previously-given meaning, and, if desired,carrying out the optional steps.

This reaction is carried out according to the previouslydescribedprocedure; the starting materials are known or may be prepared accordingto procedures used for the known compounds.

The compounds of this invention may also be obtained by converting in a1,4-benzodioxane Z-carboxylic acid cycloaliphatic-lower alkyl-amide,particularly in a compound of the formula R CONH(C l-I )R in which R Rand n have the previously-given meaning, the carbonyl group intomethylene, and, if desired, carrying out the optional steps.

Conversion of the carbonyl portion of the amide group into methylene iscarried out according to known methods, particularly by treatment with areducing reagent capable of converting the carbonyl portion of the amidegrouping into methylene. Such reducing agents are especially alkalimetal aluminum hydrides or alkaline earth metal aluminum hydrides,particularly lithium aluminum hydride, as well as sodium aluminumhydride, magnesium aluminum hydride and the like; if desired, thesereagents may be used in the presence of an activator, for example,aluminum chloride and the like. The reaction is carried out in thepresence of a suitable solvent, for example, an ether, e.g.diethylether, tetrahydrofuran and the'like, and, if necessary, at anelevated temperature, for example, at the refluxing temperature of thesolvent. The amine may also be obtained by electrolytically reducing theamide on a suitable cathode, such as mercury, lead, nickel cathode andthe like, using a proper anode and suitable catholyte and anolyte media.Conversion of the carbonyl portion in an amide group into methylene mayalso be carried out by treatment with hydrogen in the presence of asuitable catalyst, e.g. certain copper catalysts and the like.

The starting materials used in the above reaction may be preparedaccording to procedures generally used for the preparation of carboxylicacid amides, for example,

by treatment of an acid halide, e.g. chloride, with an amine.

Compounds of this invention, particularly those of the formula I inwhich R R and the letter n have the previously-given meaning, or saltsthereof, may also be obtained by converting in a cycloaliphatichydrocarbon-carboxylic acid 2-(1,4-benzodioxanyl)-rnethyl-amide or in acyclo-aliphatic hydrocarbon-lower alkane carboxylic acid 2-(1,4-benzodioxanyl)-n1ethyl-amide, particularly in a compound having theformula in which R R and the letter n have the previouslygiven meaning,the carbonyl group into methylene, and, if desired, carrying out theoptional steps.

The above reaction is carried out according to the previously-describedmethods, and the starting materials are prepared according to knwonprocedures.

The compounds of the present invention may also be prepared byconverting in a 1,4-benzodioxane 2-thiocarboxylic acid cycloaliphatichydrocarbon-lower alkylamide, particularly in a compound of the formulain which R R and the letter 11 have the previously-given meaning, thethiocarbonyl group into methylene, and, if desired, carrying out theoptional steps.

The above conversion may be carried out according to known methods, forexample, by treating the thioamide compound with freshly prepared Raneynickel in a suitable, particularly in an alcoholic, solvent, e.g.methanol, ethanol and the like, or electrolytically reducing itaccording to the procedure outlined hereinabove for the reduction of theamides.

The starting materials may be prepared, for example, from thepreviously-described amides by treatment with 1stllitable reagents, e.g.phosphorus pentasulfide and the ice.

Another method for the preparation of compounds of this invention,particularly of compounds having the formula in which R R and the letter11 have the previously-given meaning, comprises converting in acycloaliphatic hydrocarbon thiocarboxylic acid2-(1,4-benzodioxanyl)-methyl-amide or in a cycloaliphatichydrocarbon-lower alkane thiocarboxylic acid 2-( 1,4-benzodioxanyl-methyl-amide, particularly in a compound having the formula in which RR and the letter n have the previously-given meaning, the thiocarbonylgroup into methylene, and, if desired, carrying out the optional steps.

The above procedure is carried out as shown hereinbefore, and thestarting material is prepared according to known methods.

Compounds of this invention, particularly those of the formula in whichR R and the letter 11 have the previously-given meaning, or saltsthereof, may also be obtained by removing in anN-[2-(1,4-benzodioxanyl)-methyl]-N-cycloaliphatic hydrocarbon-loweralkylidene-amine, particularly in a compound of the formula in which R Rand the letter 11 have the previously-given meaning, the Schilfbase-type C=N-double bond by re duction, and, if desired, carrying outthe optional steps.

The reduction of the Schiif base-type double bond may be carried out byusing catalytically activated hydrogen or a di-light metal hydride ashydrogenating agents. Catalysts containing a metal of the eighth groupof the Periodic System may be used in the presence of hydrogen; forexample, palladium, e.g. palladium on charcoal and the like, representsa suitable metal catalyst. The reduction is carried out by treating, forexample, a lower alkanol, cg. methanol, ethanol and the like, solutionof the Schitf base with hydrogen, if desired, at an increased pressure,in the presence of the catalyst.

The preferred reduction reagents, however, are light metal hydrides,particularly the alkali metal borohydrides, e.g. lithium borohydride,sodium borohydride and the like, as well as alkali metal aluminumhydrides, e.g. lithium aluminum hydride, sodium aluminum hydride and thelike, alkaline earth metal aluminum hydrides, e.g. magnesium aluminumhydride and the like, or any other suitable light metal hydride. Thereduction with these reagents is preferably carried in solution, thesolvents being chosen according to the reactivity of the reagent. Forexample, an alcohol, such as a lower alkanol, e.g. methanol, ethanol,isopropanol and the like, if desired, aqueous mixtures thereof, and thelike may be used with an alkali metal borohydride; an ether, e.g.diethylether, tetrahydrofurane and the like, is used with an alkalimetal aluminum hydride. If desired, the reaction may be promoted by theaddition of an activator, for example, of aluminum chloride and thelike. The reaction is performed at room temperature or preferably at anelevated temperature, for example, at the boiling temperature of thesolvent, and, if necessary, in the atmos phere of an inactive gas, e.g.nitrogen.

The Schiff base-type starting materials may be prepared according tomethods known per se, for example, by reacting a2-benzodioxanylmethyl-amine with a cycloaliphatic hydrocarboncarboxaldehyde or with a cycloaliphatic hydrocarbon-lower alkanecarboxaldehyde, if necessary, in the presence of a solvent, such as analcohol, for example, a lower alkanol, e.g. methanol, ethanol and thelike, and/ or under cooling at room temperature or at an elevatedtemperature.

The compounds of this invention may also be prepared by removing in anN-[2-(1,4-benzodioxanyl)-methylene]- N-cycloaliphatic hydrocarbon-loweralkyl-amine, particularly in a compound of the formula in which R R andthe letter n have the previously-given meaning, the Schiif base-typeC=N-double bond by reduction, and, if desired, carrying out the optionalsteps.

The reductive removal of the Schilf base-type double bond is carried outas previously shown; the starting material is prepared according toknown methods.

Depending on the conditions used in new compounds of this invention maybe obtained in the form of the free bases or as the salts thereof. Asalt may be converted into the free base in the customary way, forexample, by reaction with an alkaline reagent, such as an alkali metalhydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, analkali metal carbonate, e.g. sodium or potassium carbonate or hydrogencarbonate and the like, ammonia and the like, or with a suitable anionexchange resin. A free base may be converted into an acid addition saltby reacting it or a solution thereof in a suitable solvent with theappropriate inorganic or organic acid, such as one of those outlinedhereinbefore, or a solution thereof. Salts may also be converted intoother salts directly; for example, a hydrobromic may be converted intothe hydrochloride or maleate by treating an aqueous solution oftheformer with an alkali metal chloride, e.g. sodium chloride and the like,or with a monoalkali metal salt of maleic acid, e.g. mono-sodium maleateand the like, and isolating the desired salt.

The invention also comprises any modification of the process wherein acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining step(s) of the processis(are) carried out, as well as any new intermediates.

In the process of the invention such starting materials are preferablyused which lead to final products mentioned in the beginning aspreferred embodiments of the invention.

This is a continuation-in-part application of my application Serial No.142,507, filed October 3, 1961, which in turn is a continuation-in-partapplication of my application Serial No. 103,210, filed April 17, 1961,both now abandoned.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees ccntigrade.

Example I which is recrystallized from ethanol, MI. 25(l-252; yield: 36percent.

Example 2 A mixture of 4.75 g. of cyclopentylmethylamine and 2.9 g. of2-chloromethyl-l,4-benzodioxane in 15 ml. of ethanol is reactedaccording to the method shown in Example 1 to yield the2-(cyclopentylmethylaminomethyl)- 1,4-benzodioxane hydrochloride of theformula which melts at 2l7219; yield: 42 percent.

Example 3 A mixture of 9.6 g. of 3-cyclopentylpropylamine and 4.2 g. of2-chloromethyl-1,4-benzodioxane in 25 ml. of ethanol, when reacted asdescribed in Example 1, yields the 2-[(3-cyclopentylpropyl)-aminomethyl]-1,4-benzodioxane hydrochloride of theformula C on-crnN1r-cu:om-On2 n01 0 which melts at 245246; yield: 64percent.

Example 4 A mixture of 9.0 g. of Z-cyclohexylethylamine and 3.8 g. of2-chloromethyl-1,4-benzodioxane in 20 ml. of ethanol, when heated in asealed tube and worked up according to the method shown in Example 1,yields the 2-[(2- cyclohexylethyl) -aminomethyl] -1,4-benzodioxanehydrochloride of the formula which melts at 263265; yield: 72 percent.

9 Example 5 I A mixture of 8.5 g. of 3-cyclohexylpropylamine and 3.7 g.of 2-chloromethyl-1,4-benzodioxane in 20. ml. of ethanol yields the 2-[(3-cyclohexylpropyl)-aminomethyl]- 1,4-benzodioxane hydrochloride of theformula when reacted according to the procedure of Example 1, and meltsat 234-237 yield: 71 percent.

Example 6 A mixture of 3.7 g. of 2-chloromethyl-1,4benzodioxane and 8.4g. of 2-cycloheptylethyl-amine in 15 ml. of ethanol is reacted as shownin Example 1; the resulting 2-[(2- cycloheptylethyl)aminoethyl]-1,4-benzodioxane hydrochloride melts at 247-251 yield: 2.5g.

Example 7 A solution of 3.0 g. of a mixture of Z-chloromethyl--methoxy-1,4-benzodioxane and 2-chloromethyl-8-methoxy-l,4-benzodioxaneand 4.8 g. of 2-cyclopentylethylamine in 15 ml. of ethanol is heated ina sealed tube to 150 for four hours. The reaction mixture isconcentrated and taken up in diethylether and water. The organicsolution is separated, washed, dried and evaporated. The residue isdissolved in ethyl acetate, anhydrous hydrogen chloride as passedthrough the solution and the precipitate is collected. The resultingcompound is the 2-[ (2- cyclopentylethyl) aminomethyl]8-methoxy-1,4-benzodioxane hydrochloride, M.P. 161-165"; yield: 1.7 g.

Example 8 with diethyl ether and filtered off, M.P. 135437"; yield:-

3.3 g. The hydrochloride is prepared by treating an ethanol solution ofthe free base with anhydrous hydrogen halide. The 2[(2-cyclopentylethyl)-aminomethyl]-8-hydroxy-l,4-benzodioxanehydrochloride melts above 275;

yield: 3.3 g.

Example 9 A solution of 4.4 g. of a mixture of 5-benzyloxy-2-chloromethyl-1,4-benzodioxane andS-benzyloxy-Z-chloromethyl-l,4-benzodioxane and 5.1 g. ofZ-cyclopentylethylamine in 25 ml. of ethanol is heated in a sealed tubeto 150 for four hours; the reaction mixture is Worked up as shown inExample 1. The hydrochloride is pre pared by passing anhydrous hydrogenchloride through a solution of the free base in ethyl acetate. 2.6 g. of5- benzyloxy 2-[(2 cyclopentylethyl) aminomethyl]-1,4- benzodioxanehydrochloride precipitates and is recrystallized from isopropanol, M.P.218-220"; yield: 0.9 g. The ethyl acetate mother liquor is allowed tostand and yields 1.1 g. of 8-benzyloxy-2-[(2-cyclopentylethyl)-aminomethyl]-l,4-benzodioxane hydrochloride, which is recrystallizedfrom isopropanol, M.P. 179-180".

The starting materials may be prepared as follows: A mixture of 10.0 g.of a mixture of 2-chloromethyl-5- hydroxy-1,4-benzodioxane and2-chloromethyl-8-hydroxy- Example 10 A solution of 7.1 g. of the mixtureof two isomeric benz-acetyl-2-chloromethyl-1,4-benzodioxanes and 10.5 g.of 2-cyclopentylethyl-amine in 50 ml. of ethanol is heated in a sealedtube for four hours at The reaction mixture is concentrated, water anddiethylether are added; the organic phase is separated, washed withwater, dried and evaporated to dryness. The residue is dissolved inethyl acetate, dry hydrogen chloride is added and the resulting crudeproduct is filtered off and extracted with isopropanol; after cooling,3.6 g. of a solid material is isolated and recrystallized from ethanolto yield 1.0 g. of benz acetyl 2 (2 cyclopentylethyl-aminomethyl)-1,4-benzodioxane (isomer 1) hydrochloride, M.P. 217-219".

The isopropanol filtrate is evaporated to dryness, the residue isextracted with water, and the mixture is cooled, whereupon an oilseparates. The latter is extracted with ethyl acetate the aqueoussolution is made alkaline with sodium hydroxide, and the organicmaterial is extracted with ethyl acetate. The organic solution is driedand evaporated, and the residue is distilled; yield: 0.8 g. of benzacetyl 2 (2 cyclopentylethyl-aminomethyl)-1,4- benzodioxane (isomer II)of the formula O I-IOHz-NCH2 CHE-CH O CH2CH2 which is converted into itshydrochloride, M.P. -158, by treating an ethyl acetate solution of thefree base with a concentrated solution of hydrogen chloride in ethylacetate.

The starting material may be prepared as follows: To a solution of 18.5g. of 2-chloromethyl-1,4benzodioxane and 9.0 g. of acetyl chloride in 70ml. of carbon disulfide is added 13.3 g. of aluminum chloride over aperiod of thirty minutes while. stirring. After the evolution ofhydrogen chloride has slowed down, the reaction mixture is heated on thesteam bath for thirty minutes and is then cooled and treated with amixture of ice and water. The water and carbon disulfide layer aredecanted from the solid material which is taken up in diethyl ether andwater. The organic solution is then separated, washed with water, driedand evaporated. The residue is distilled under reduced pressure to yield7.1 g. of a mixture of two isomeric benz-acetyl-1,4-benzodioxanes, whichis collected at 148/0.5 mm., and is used without separating the isomericcompounds.

Other compounds, such as, for example, 2-(cyclopropylmethylaminomethyl)benzodioxane, 2[(2-cyclo propylethyl) aminomethyl]-benzodioxane,2-[(2-cyclobutylethyl) aminornethyl]-benzodioxane,2-(cycloheptylmethylaminomethyl -benzodioxane, 2-[ (2-cycloheptylethyl)-aminomethyl] -benzodioxane, 2- 2-cyclo-octylethyl) aminomethyl]3-methyl-benzodioxane, 2-(cyclopentylmethylaminomethyl-5methyl-benzodioxane, 2- (2-cyclopentylethyl)aminomethyl]-8-ethoxy-benzodioxane, 2-

(cyclohexylmethylaminomethyl) 5 chloro-benzodiox ane, 2[(2-cyclohexylethyl)-aminomethyl]-8-methoxybenzodioxane, 2-{ [2-(l-cyclohexenyl) -ethyl]-aminomethyl}-benzodioxane, 2-{ [2-l-cycloheptenyl) -ethyl] aminomethyl}-benzodioxane and the like, orsalts thereof, may be prepared according to the above procedure.

austere l l. Example 11 A mixture of 6.6 g. of7-aceryl-2-(4-bromo-phenylsulfonyloxy-methyl)-l,4-benzodioxane, 66 ml.of acetonitrile and 3.3 g. of 2-cyclopentylethylamine is refluxed for 19hours. After cooling, the precipitate is filtered off, and the filtrateis evaporated to dryness. The residue is dissolved in ethyl acetate, 21small amount of insoluble material is filtered off and the filtrate istreated with a small amount of a concentrated solution of hydrogen chlride in dry ethyl acetate. The crystalline 7-acetyl-2-[(Z-cyclopentylethyl) aminomethyl] -l,4-benzodioxane hydrochloride ofthe formula precipitates; it melts at 156160 (yield: 3.5 g.) and isidentical with the hydrochloride of the bcnz-acetyl-2-[(2-cyclopentylethyl) aminornethyl]-l,4-benzodioxane (isomer ll) of Example10.

The starting material used in the above procedure is prepared asfollows: To a solution of 39.9 g. of sodium hydroxide in 345 ml. ofwater is added 69 g. of 3,4-dihydroxy-acetophenone, the solution iscooled to while maintaining an atmosphere of nitrogen. Over a period ofninety minutes, a solution of 95 g. of phosgene in 400 ml. of toluene isadded dropwise while maintaining the temperature of the reaction mixtureat 0. After about one-half of the phosgene solution has been added, thepH of the solution has become neutral; an additional solution of g. ofsodium hydroxide in 180 ml. of water is, therefore, added in portions.Upon completion of the phosgene addition, the reaction mixture isstirred for one hour in an ice-bath, and is then filtered; the twolayers are separated, and the toluene solution is evaporated to dryness.The residue is combined with the solid material previously filtered ofi.The crude product is extracted twice with about 200 ml. of ethanol atroom temperature to yield 58 g. of 4-acetyl-o-phenylene carbonate, M.P.l08llO.5.

A mixture of 50 g. of 4-acetyl-o-phenylene carbonate in 500 ml. ofmethanol is refluxed for three hours while stirring. The solvent isremoved under reduced pressure and the residue is allowed tocrystallize. The desired 3-acetyl-6-hydroxy-phenyl methyl carbonate isrecrystallized by dissolving it in isopropanol while heating anddiluting the solution with two volumes of hexane, M.P. l27129; yield:41.3 g.

A mixture of 32 g. of 3-acetyl-6-hydroxy-phenyl methyl carbonate, 42.2g. of epichlorohydrin and 0.3 ml. of piperidine is heated for one houron the steam bath; an additional five drops of piperidine is added,heating is continued, and after one hour, again five drops of piperidineare added. After a total heating time of seven hours, the unreactedepichlorohydrin is removed by distillation under reduced pressure; theresidue is dissolved in chloroform and 20 ml. of concentratedhydrochloric acid are added. After standing for 4 /2 hours at roomtemperature with occasional agitation, the organic solution isseparated, washed twice with Water, dried and concentrated under reducedpressure. The residue is dissolved in 50 ml. of ethanol and added to asolution of g. of potassium hydroxide in 60 ml. of water. The reactionmixture becomes warm, and potassium chloride precipitates. Afterstanding at room temperature for thirty minutes, ethyl acetate is added,and the resulting solution is washed twice with 200 ml. of water. Afterdrying over sodium sulfate, the solution is evaporated to dryness; theoily residue is dissolved in ml. of ethanol and on standing, the3,4-bis-(2,3-cpoxypropyloxy)-acetophenone precipitates and is filteredoff, yield:

12 8.6 g. The pure product melts at 94-96 after recrystallization fromethanol.

The ethanol mother liquors are concentrated and the residue is distilledunder reduced pressure; the desired 7-acetyl-Z-hydroxymethyl-1,4-ber1zodioxane is collected at 176/O.1 mm.;yield: 14- g.

A solution of 4.0 g. of 7-acctyl-2-hydroxymethyl-1,4- benzodioxane in 20ml. of pyridine is treated with 6.4 g. of p-bromo-benzcne sulfonylchloride. The reaction m"'ture is allowed to stand at room temperatureover night and is then poured onto a mixture of ice and water. Theaqueous layer is decanted; the oily precipitate is dissolved inchloroform and the chloroform solution is washed with dilutehydrochloric acid and water and is dried and concentrated to yield 6.5g. of the crude prodnot. The latter is repeatedly extracted with 25 ml.portions of hot ethanol; on cooling the desired 7-acetyl-2-(4- bromophenyl sulfonyloxy-methyl)-l,4-benzodioxane crystallizes L ad isrecrystallized from methanol, M1. 127.

Into the carbocyclic aryl portion of the 1,4-benzodioxane nucleus of aresulting compound, a substituent may be introduced. For example, uponnitration with a suitable nitrating reagent, a nitro group may beintroduced. Gr, 21 resulting compound may be reacted with an organiccarboxylic acid halide, e.g. chloride and the like, in the presence of asuitable reagent, such as aluminum chloride and the like, and an organiccarboxylic acid acyl radical may be introduced.

Certain substituents attached to the carhocyclic aryl portion of the1,4-bon2otlioxane nucleus may be converted into other stituents. Forexample, a nitro group may be reduced to an amino group according toknown reduction methods, for example, by controlled treatment withhydrogen in the presence of a suitable catalyst, e.g. palladium oncharcoal and the like, and of an inert solvent, cg. pdioxane and thelike. An amino group may be conv: ted into a halogeno atom bydiazotization, followed neat with a Cuprous halide according to theSandmeyer leaction. Or, a lower allioxy, e.g. methoxy and the like,group may be converted into a free hydroxyl group, for example, byacidic hydrolysis with hydrobromic acid in the presence of acetic acidand the like.

What is claimed is:

l. A member selected from the group consisting of a compound of theformula in which is a member selected from the group consisting ofhydrogen and lower allzyl, the letter it stands for a whole number fromone to seven, R stands for a member selected from the group consistingof cycloalkyl having from three to eight ring carbon atoms andcycloalkenyl having from five to eight ring carbon atoms, and Ph standsfor a member selected from the group consisting of l,2- phenylene, loweralkyl-LZ-phenylene, hydroxy-l,2-phenylene, lower all-:oxy-l,2-phenylene,phenyl-lower alltoxy-l, 2-phenylene, halogeno-LZ-phenylen and loweralltanoyl- 1,2-phenylene, and pharmaceutically acceptable acid additionsalts thereof.

2. A compound of the formula F err-CH --NH(Gamma-m O in which Rrepresents cycloalltyl having from three to eight carbon atoms, and theletter 11 stands for a whole number from one to four.

s,157,ev4

3. The pharmaceutically acceptable acid addition salt of a compound ofthe formula 0 OHz H-CHg-NH(O1;'Hzn')R in which R represents cycloalkylhaving from three to eight carbon atoms, and the letter It stands for aWhole number from one to four.

4. 2 [(2 cyclopentylethyl) aminomethyl] benzodioxane.

5. 2-(cyclopentylmethylarninomethyl)-benzo-dioxane.

6. 2 [(3 cyclopentylpropyl) aminomethyl1- benzodioxane.

7. 2- (2-cyclohexylethyl -an1inomethyl] -henzodioxane.

8. 2 [(3 cyclohexylp-ropyl) aminomethyl] benzodioxane.

9. A compound of the formula 14 in. which R represents cycloalkyl havingfrom three to eight carbon atoms, the letter )1 stands for a wholenumher from one to four, and R stands for lower alkanoyl.

1G. The pharmaceutically acceptable acid addition salt of a compound ofthe formula No references cited.

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA